The term bronchial hyperresponsiveness is generally used to describe a heightened airway smooth muscle bronchoconstrictor response measured by bronchoprovocation testing. However, the airway also responds to inflammation or bronchoprovocation with increased mucus secretion. We use the term “secretory hyperresponsiveness” to mean increased mucus secretion either intrinsically or in response to bronchoprovocation. This is not the same as retained phlegm or sputum. Unlike smooth muscle contraction, which is rapidly reversible using a bronchodilator, mucus hypersecretion produces airflow limitation that reverses more slowly and depends upon secretion clearance from the airway. Certain groups of patients appear to have greater mucus secretory response, including those with middle lobe syndrome, cough-dominant (“cough-variant”) asthma, and severe asthma. Secretory hyperresponsiveness also is a component of forms of lung cancer associated with bronchorrhea. An extreme form of secretory hyperresponsiveness may lead to plastic bronchitis, a disease characterized by rigid branching mucus casts that obstruct the airway. Secretory hyperresponsiveness and mucus hypersecretion appear to be related to activation of the extracellular-regulated kinase 1/2, signaling through the epidermal growth factor receptor, or secretory phospholipases A2. Recognizing secretory hyperresponsiveness as a distinct clinical entity may lead to more effective and targeted therapy for these diseases.